Submissions for variant NM_000152.5(GAA):c.1326+1G>A

gnomAD frequency: 0.00003  dbSNP: rs1205507761

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001249034	SCV002817440	pathogenic	Glycogen storage disease, type II	2022-10-17	reviewed by expert panel	curation	The NM_000152.5:c.1326+1G>A variant in GAA is a canonical splice site variant in the donor splice site of intron 8. RT-PCR evidence suggests that the variant results in nonsense-mediated decay (PMID: 10189220) (PVS1). Two African-American patients with infantile-onset Pompe disease have been reported with this variant. GAA activity is available for one of these patients and was 0.35% in fibroblasts (PMID: 10189220) (PP4_Moderate). These patients are compound heterozygous for the variant and either c.1441T>C (p.Trp481Arg) or c.1555A>G (p.Met519Val) (PMID: 10189220, 25256446). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Therefore, PM3 is not met at the current time. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000114 (1/8708 alleles) in the African/ African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is ClinVar entry to this variant (Variant ID: 597944). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PP4_moderate, PM2_supporting. (Classification approved by the ClinGen LSD VCEP on October 17, 2022).
Eurofins Ntd Llc (ga)	RCV000734207	SCV000862331	pathogenic	not provided	2018-07-20	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249034	SCV001422969	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.1326+1G>A variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 22644586, 10189220) and has been identified in 0.01% (1/8708) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1205507761). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as Pathogenic by EGL Genetic Diagnostics (VariationID: 597944). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. There is an in-frame cryptic splice site 6 bases from the intron-exon boundary, providing evidence that this variant may delete 2 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. The phenotype of an individual that is compound heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <1% of wild type consistent with disease (PMID: 25256446). This variant has been seen in combination with the reported pathogenic variant p.Met519Val (PMID: 25256446) in individuals with glycogen storage disease II. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PM2, PP4 (Richards 2015).
AiLife Diagnostics, AiLife Diagnostics	RCV000734207	SCV002501119	likely pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249034	SCV004296867	pathogenic	Glycogen storage disease, type II	2024-09-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with glycogen storage disease type II (PMID: 10189220). This variant is also known as IVS8 g+1a. ClinVar contains an entry for this variant (Variation ID: 597944). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249034	SCV005395048	pathogenic	Glycogen storage disease, type II	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1326+1G>A (also described as IVS8 g+1a in the literature) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of GAA function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant resuls in lack of mRNA from the mutant allele (Raben_1998). The variant was absent in 200502 control chromosomes (gnomAD). c.1326+1G>A has been reported in the literature in individuals affected with infantile onset glycogen storage disease, type 2 (Pompe Disease) (Raben_1998). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 10189220). ClinVar contains an entry for this variant (Variation ID: 597944). Based on the evidence outlined above, the variant was classified as pathogenic.